Macrophages have functions of clearing wastes in a body and of defending against pathogens including microorganisms and viruses or tumor cells. It displays antigens for T cells and produces interleukin-1, and thereby functions as an effector of cell-mediated immunity. Thus, it is important to activate macrophages for treatment of infectious diseases or cancers.
Interferon is one of the macrophage-activating factors and has been used for clinical trials. In addition, it is known that some kinds of polysaccharides have an ability to activate immune response and some of them have been developed as an anti-virus agent or anti-cancer agent (Japanese Patent Laid-open publication No. 05-097695 or Japanese Patent No.06-099314). However, it has hardly been tried to activate macrophages using an antibody.
A gene for human signal regulatory protein β (SIRPβ) has been cloned and SIRPβ was predicted to be a transmembrane protein having an extracellular domain with three Ig-like domains and a short intracellular domain from its deduced amino acid sequence (Nature, 1997, vol. 386, p181-186). The gene for SIRPβ was cloned based on a homology with signal regulatory protein α (SIRPα; also called as SHPS-1), however, physiological role of SIRPβ has not been elucidated because SIRPβ does not have YXX (L/V/I) motief which is a tyrosine-phosphorylation site and to which SH2 domain of proteins such as SHP-1 binds, contrary to SIRPα.
An antibody which recognizes an extracellular domain of SIRPα has been used for inhibiting macrophage-mediated phagocytosis (WO 00/66159). On the other hand, an antibody which recognizes an extracellular domain of SIRPβ has been produced and used for a research purpose (Blood, 2001, Vol. 97, No. 9, p. 2741-2749). However, such an antibody has never been used for activating macrophages, since physiological role of SIRPβ has not been known.